Calcium. Calcium, a physiologically essential mineral, plays a central role in building stronger, denser bones early in life and in maintaining strong and healthy bones later in life. In addition, calcium functions in cardiac regulation, blood clotting, nerve signal conduction, stimulating hormone secretion, muscle contraction, and other diverse physiological processes.
In the absence of calcitriol, intestinal absorption of calcium is solely by the passive, extracellular route, which limits gross absorption from the gastrointestinal tract to about 10% of dietary intake. Absorption results in transient serum hypercalcemia, and about half of the calcium absorbed from the gastrointestinal tract spills into the urine and is excreted. Concurrently, the body loses calcium through skin, nails, hair, sweat, and excretion. Dermal losses of calcium in sweat are unregulated. Under sedentary conditions, cutaneous losses alone are estimated to be on the order of 0.4 to 1.4 mmol calcium per day, but with exercise and sweating, such losses can rise to above 7 mmol calcium per day. This drain is great enough to produce a measurable change in bone mass across an athletic playing season, for example. The lost calcium must be replaced, or the body will take calcium from the bones to perform other functions.
It is well known that augmented calcium intakes build and maintain peak bone mass, structure and quality during growth and repair; slow age-related bone loss; prevent fractures resulting from osteoporosis; and reduce fragility fractures in the elderly. Moreover, there is general agreement that a high peak bone mass is strong protection against low bone mass and its associated fragility later in life.
Vitamin D. Vitamin D, not a normal constituent of most foods, is typically produced endogenously by a cutaneous photosynthetic reaction. Solar ultraviolet radiation converts endogenous 7-dehydrocholesterol into pre-vitamin D3, which then rapidly isomerizes in the skin to cholecalciferol (vitamin D3). Cholecalciferol is stored bound to D-binding protein. Upon release from storage, cholecalciferol is converted to 25-hydroxy vitamin D3 [25(OH)D3; ergocalciferol] in the liver and kidneys. Subsequently, 25(OH)D3 is hydroxylated in the kidney to 1,25(OH)2D3 (calcitriol). Calcitriol functions as a hormone, enhancing calcium absorption by binding to a mucosal nuclear receptor and inducing the synthesis of calcium-binding transport protein needed for active calcium absorption across the intestinal mucosa. In addition, 25(OH)D3 plays a role in calcium and magnesium transport by binding to mucosal receptors and augmenting active transport in cells in which calcium- and magnesium-binding proteins have been expressed.
Vitamin D plays an essential role in calcium and magnesium homeostasis. In addition, vitamin D is essential for optimal physiological functioning of a spectrum of other cells and tissues, including the brain. Other functions of vitamin D include regulation of proliferative and apoptotic activity, immunomodulatory and prodifferentiation activity, and interaction with the rennin-angiotensin system, insulin secretion, and neuroprotective activity.
Vitamin D status is currently indicated by 25-hydroxycholecalciferol (25OHD3) concentration in serum. The National Academy of Sciences (NAS) used a cutoff value of 27.5 mmol/L (<11 ng/mL) 25OHD3 to indicate “vitamin D deficiency” for the purposes of setting Dietary Reference Intakes for vitamin D.
Magnesium. Magnesium is the fourth most prevalent element in the body and the second most abundant intracellular ion. Since magnesium is a cofactor in over 300 enzyme systems, adequate magnesium is essential for many biosynthetic processes, glycolysis, formation of adenosine-3″,5″-cyclic monophosphate, energy-dependent membrane transport, and transmission of the genetic code. Magnesium makes up 0.5-1% of the bone and plays a role in both matrix and mineral metabolism in bone. Magnesium depletion causes cessation of bone growth, decreased osteoblastic and osteoclastic activity, osteopenia, and bone fragility. Patients with significant magnesium deficiency experience tremors, myoclonus, and arrhythmias including ventricular tachycardia, fibrillation, and torsade de pointes.
Adequate serum magnesium levels are needed for proper calcium metabolism. Magnesium deficiency can result in calcium deficiency, peripheral resistance to the effects of vitamin D, and resistance to parathyroid hormone. As a result, adequate calcium intake may not ensure proper bone health if magnesium status is abnormal. Further, under conditions of chronic magnesium insufficiency, although serum magnesium levels are in the low normal range, intracellular magnesium levels may be insufficient to support health.
Bone Health. Bone is not a hard and lifeless structure. It is, in fact, complex, living tissue. Bone breakdown and new bone formation is continuous, and natural changes in bone health reflect the balance between these processes. During youth, bones grow in length and density. During teen years, maximum height is obtained, and almost 40% of adult bone mass is potentially accrued. Bones continue to grow more dense until about age 30 when peak bone density is attained. After that point, bones slowly start to lose density or strength as bones begin to break down faster than new bone can be formed. This imbalance occurs as part of the natural aging process; or as the result of prolonged exposure to certain medications (e.g., steroids, anticonvulsants, certain cancer treatments, and aluminum-containing antacids); chronic disease that affects the kidneys, lungs, stomach, and intestines; or lifestyle habits at any age. Therefore, it is important to optimize bone development and maintenance throughout life by incorporating sufficient calcium, magnesium, and phosphate for bone health in the diet, both as food and as supplements.
Osteoporosis. Osteoporosis is a disease of bone leading to an increased risk of fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old sex-matched healthy person average) as measured by dual energy x-ray absorptiometry. Osteoporosis is most common in women after the menopause, but may develop in men and pre-menopausal women if they suffer from hormonal disorders and other chronic diseases, smoke, or use medications that interfere with calcium absorption.
According to the Surgeon General, osteoporosis and other bone diseases can initiate a downward spiral in physical health and quality of life. Bone disease can also lead to premature death. The 2004 report, Bone Health and Osteoporosis: A Report of the Surgeon General, stated that 10 million Americans over the age of 50 have osteoporosis, while another 34 million are at risk for developing the disease. [U.S. Department of Health and Human Services, Public Health Service, Office of the Surgeon General, Bone Health and Osteoporosis: A Report of the Surgeon General, 2004] The disease has been implicated as a causative factor in 1.5 million bone fractures each year. In the 2004 report, the Surgeon General warned that by 2020, half of all Americans older than 50 will be at risk for fractures from osteoporosis and low bone mass if no immediate action is taken.
Dose and Form of Conventional Vitamin and Mineral Compositions Supporting Bone Health. Calcium, concurrently supplied with vitamin D, maintains bone health, enables optimal bone growth, and is useful for the prevention and treatment of osteoporosis. As a consequence, calcium with vitamin D is among the most commonly prescribed dietary supplements. The main indication for these prescriptions is the prevention or treatment of osteoporosis and osteoporotic fracture (a bone fracture resulting from severely decreased bone density and debilitating alterations in bone microarchitecture). For example, in a recent randomized, controlled trial of calcium (1 gram calcium/day as the citrate) in 1,471 healthy older women (aged 74+/−4 years), supplemental calcium had a beneficial effect on bone density, reduced fracture incidence, hazard ratios on time to first fracture, and prevention of height loss. [Reid I R, Mason B, Horne A, Ames R, Reid H E, Bava U, Boiland M J, Gamble G D. Randomized controlled trial of calcium in older women. Am J Med 2006; 119(9): 777-785] Likewise, a meta-analysis was carried out of 29 studies in which calcium and/or vitamin D were administered to individuals at age 50 or older. A total of 63,897 subjects were examined in these trials, with a mean age of 67.8 years for all subjects; 92% were women. The analysis showed that both the dose of calcium and the form in which it is provided are significant factors in maintaining bone health. The minimum dose of calcium which appears to be effective is 1200 mg daily. The overall rate of fracture reduction associated with calcium or calcium plus vitamin D supplementation versus placebo was 12% (P=0.0004). The active intervention was associated with a reduced bone loss of 0.54% at the hip and 1.19% at the spine. Greater treatment adherence strengthened the positive outcomes associated with active treatment. Individuals over the age of 70 were particularly likely to benefit from supplementation with calcium alone or calcium plus vitamin D. A second meta-analysis showed that the dose of vitamin D was a significant factor in maintaining bone health, particularly at non-vertebral sites. Researchers analyzed data from 12 randomized, controlled trials and found that vitamin D at a dose of 700 to 800 IU per day reduced the risk of hip fracture by 26% and any non-vertebral fracture by 23%. Both of these results were statistically significant. However, the data showed that vitamin D at a dose of 400 IU per day failed to demonstrate any fracture benefit.
In general, the selection of a calcium supplement is determined by factors such as availability, purity, absorbability, and an individual's tolerance to adverse taste, texture, and side effects of ingestion. Conventionally, several different calcium compounds (Table 1) are used in supplements and therapies for supporting bone health and preventing or treating osteoporosis. The bioavailability of each of these conventional calcium sources is about 10% in the absence of vitamin D. [Heaney R P, Roecker R R, Weaver C M. Absorbability of calcium sources: the limited role of solubility. Calcif Tissue Int 1990; 46: 300-304.]
TABLE 1Conventional Calcium SourcesCalcium Source% Ca, by weightCalcium Acetate23%Calcium Carbonate40%Calcium Citrate21%Calcium Citrate Malate24%Calcium Gluconate 9%Calcium Lactate14%“Calcium Phosphate”34-40%
Of the calcium salts listed in Table 1, calcium carbonate contains the highest percentage of calcium by weight (40%) and is the least expensive and most widely used at the present time. However, it is one of the most poorly absorbed and least bioavailable of calcium salts, particularly when administered in high doses. In addition, it is one of the most unpalatable of calcium salts and has a repugnant chalky taste. Further, calcium carbonate often contains trace quantities of toxic metals such as lead, thallium, and aluminum. Alternatively, calcium is conventionally supplied as calcium acetate or calcium citrate. Calcium acetate contains 23% calcium by weight. While it is more palatable than calcium carbonate, ingestion of high doses results in gastric irritation and regurgitation of acetic acid (“vinegar breath”). Calcium citrate contains 21% calcium by weight. This salt is more palatable than calcium carbonate or calcium acetate. However, doses of 1 g calcium citrate daily have been reported to increase risk for myocardial infarction, stroke and death. [Bolland M J, Barber P A, Doughty R N, Mason B, Horne A, Ames R, Gamble G D, Grey A, Reid I R. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. Brit Med J 2008 Feb. 2; 336(7638): 262-266.] Calcium phosphate, the other calcium salt with a high percentage calcium is frequently hydroxyapatite (“ground bone”) and has a distasteful appearance and chalky taste coupled with poor absorption from the gastrointestinal tract.
Vitamin D insufficiency is common in the United States. The elderly and African-Americans are at particularly high risk of deficiency. Vitamin D deficiency among the elderly causes secondary hyperparathyroidism and osteomalacia and exacerbates osteoporosis, resulting in increased risk of skeletal fractures. The prevalence of vitamin D deficiency or insufficiency, as estimated from the National Health and Nutrition Examination Survey (NHANES) III data for non-institutionalized individuals, indicated that one-half of the elderly women sampled who lived in northern latitudes had vitamin D insufficiency. The incidence among institutionalized and homebound elderly individuals, who spend less time in the sunshine, is potentially much greater.
Magnesium is absorbed in the intestines and then transported to cells and tissues throughout the body. Approximately one-third to one-half of dietary magnesium is absorbed into the body of a healthy individual. Although the percentage absorption of dietary magnesium is high, data from the 1999-2000 National Health and Nutrition Examination Survey suggest that substantial numbers of adults in the United States fail to consume diets containing the recommended amounts of magnesium. In particular, older adults, individuals with digestive or chronic malabsorptive disorders, and individuals with chronically low blood levels of calcium, by way of example, lack sufficient magnesium in the diet.
Conventional magnesium supplements provide magnesium as a salt (Table 2). Magnesium absorption is known to depend on the exact salt and preparation used, the dosage, the status of magnesium stores in the body, and hormonal factors. In general, magnesium salts that are soluble in water (e.g., magnesium chloride, magnesium citrate) are more bioavailable than water-insoluble magnesium salts. Certain magnesium preparations (e.g., magnesium sulfate and magnesium hydroxide) are known to have very poor absorption, a property used to produce their cathartic and purgative effects (e.g., diarrhea).
TABLE 2Conventional Magnesium SaltsMagnesium,Bioavailability (as%fractional absorptionMagnesium Saltby weightof administered dose)Magnesium oxide60 4%Magnesium carbonate45—Magnesium hydroxide42 4%Magnesium citrate1512%Magnesium lactate1212%Magnesium chloride1212%Magnesium sulfate10 4%Data obtained from http://ods.od.nih.gov/factsheets/magnesium.asp on 6 Jun. 2008.Bioavailability data taken from M. Firoz and M. Graber, Bioavailability of US commercial magnesium preparations. Magnesium Research 14: 257-262, 2001, and references therein.
As was true of calcium salts, magnesium salts are selected for use in conventional oral nutritional supplements on the basis of factors such as cost, availability, purity, absorbability, and an individual's tolerance to adverse taste, texture, and side effects of ingestion. Magnesium oxide is the most widely used magnesium salt in conventional supplements.
Ford and Mokdad have shown that adults who take dietary supplements ingest significantly more magnesium than those who do not. [Ford E S, Mokdad A H. Dietary magnesium intake in a national sample of U.S. adults. J Nutr 2003; 133: 2879-2882.] The study by Stendig-Lindberg et al. exemplifies the beneficial effects that may be anticipated when magnesium supplementation is used for the prevention and treatment of osteoporosis. [Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two-year controlled trial of peroral magnesium in osteoporosis. Magnesium Res 1993; 6: 155-163.] In a 2-year controlled therapeutic trial of post-menopausal women with documented osteoporosis, Stendig-Lindberg et al., reported that magnesium supplements prevented fractures and resulted in a significant increase in bone density. Daily doses started at 250 mg magnesium (610 mg magnesium hydroxide) and increased or decreased depending on individual tolerance levels to a maximum of 750 mg magnesium (1,810 mg magnesium hydroxide) daily in addition to dietary magnesium uptake estimated to be between 200 and 300 mg per day. Although there were no reported side effects of treatment and despite the apparent long-term benefit of supplementation in reducing fractures and increasing bone density, only 32% of the subjects completed the 2-year trial. Magnesium hydroxide is a white, chalky solid that absorbs moisture from saliva. Likely the distasteful, chalky taste coupled with the “pickled” sensation in the mouth and diarrhea contributed to poor compliance with the dosage regimen.
The “Achilles heel” of conventional nutritional supplements and therapies for the maintenance of bone health, optimizing bone growth, density, and microarchitecture, preventing bone fractures, and the prevention and treatment of osteoporosis is a lack of compliance with the dosage regimen. Most conventional formulations are combinations of inexpensive calcium salts and vitamin D. Despite the benefits which are known to derive from daily ingestion of one of these conventional formulations, 50% or more of the subjects fail to comply with this dosage regimen because they dislike its chalky or acid taste and the flatulence, acid regurgitation, nausea, and constipation that ensue. Further, conventional nutritional supplement formulations frequently fail to incorporate quantities of calcium, magnesium, and vitamin D sufficient to maintain bone health, and limit or preclude therapeutic response to optimize bone growth or prevent or treat osteoporosis. The present invention provides a solution to the long-felt need for useful and palatable compositions useful for bone growth, normal bone remodeling and skeletal health.